The long-term objective of this grant application is to explore modulation of physiological function of retinal neurons and to elucidate the underlying mechanisms through electrophysiological and pharmacological approaches. For the first three years, our efforts will be concentrated on the modulation of the horizontal cell activity in the teleost retina by centrifugal fibers. The work will be mainly performed on intact fish preparation, which has been developed by us for studying intracellular responses of retinal neurons. This unique preparation is advantageous over the eyecups and isolated retinas commonly used because the centrifugal pathway is intact. In teleost fish, centrifugal fibers originating in the olfactory bulb make synapses onto the interplexiform cells. Since the horizontal cell activity is modulated by the interplexiform cells in fish, it is highly possible that horizontal cells, even every retinal neuron, are potentially susceptible to central influences. First, we will explore the effects of centrifugal fibers through simultaneously monitoring of horizontal cell responses while cutting or electrically stimulating the optic nerve, as well as stimulating or cooling the olfactory bulb. This will provide the first evidence that the activity of neurons in the outer retina is modulated by central influences. As the next step, we will then try to understand if the interplexiform cell is an interneuron between centrifugal fibers and the horizontal cells, and if the centrifugal effects are solely mediated through the interplexiform cells. This will be done by examining central influences in preparations whose interplexiform cells are destroyed with 6-OHDA and studying the effects of dopamine antagonists on the centrifugal influences in normal intact preparations. Thus, we will be able to provide a complete description of how retinal function is modulated by the central nervous system.